Metformin is an antihyperglycemic agent of the biguanide class used in the treatment of non-insulin dependent diabetes mellitus (NIDDM) as well as other disorders. It is marketed as immediate release formulations in the form of its hydrochloride salt (such as Glucophage) and so-called extended release formulations (Fortamet, Glucophage XR, and Glumetza).
Metformin hydrochloride has intrinsically poor permeability in the lower portion of the gastrointestinal tract leading to absorption almost exclusively in the upper part of the gastrointestinal tract. Its oral bioavailability is in the range of 40 to 60% decreasing with increasing dosage which suggests some kind of saturable absorption process, or permeability/transit time limited absorption. It also has a very high water solubility (>300 mg/ml at 25° C.). This can lead to difficulty in providing a slow release rate from a formulation and problems in controlling the initial burst of drug from such a formulation. These two difficulties are further compounded by the high unit dose, 500 mg per tablet, usually required for metformin hydrochloride.
Extended release dosage forms that release metformin at a rate likely to provide the desired plasma levels of drug for an extended time period have been introduced in an attempt to maintain or even improve bioavailability. These formulations have had mixed results in the clinical setting.
New metformin modalities have been reported including certain sulfenylguanidine prodrugs of metformin referred to in International Patent Publication WO 2010/100337, published Sep. 10, 2010. International Patent Publication WO 2004/004774, published Jan. 15, 2004, refers to compositions of panthetine for the treatment of dyslipidemia. United States Patent Publication 2011/0257432, published Oct. 20, 2011 refers to certain metformin-cysteine prodrugs.
There still remains a great need for new metformin type compounds that have greater bioavailability, pharmacology and ease of use.